Peptide Stapling
Peptide stapling covalently ties two side chains of a helical peptide together with a synthetic brace, locking the helix in place to improve target affinity, protease resistance and cell entry.
Stapling is a constraint chemistry. A short peptide that is helical only when bound is mostly disordered in solution and pays an entropic penalty every time it folds to bind. Stapling removes that penalty by covalently bridging two residues that sit on the same face of the helix, most often across a single turn at positions i and i plus four, or across two turns at i and i plus seven. The classic implementation installs alpha-methyl, alpha-alkenyl amino acids at those positions and joins them by ruthenium-catalysed ring-closing metathesis, leaving an all-hydrocarbon brace, though lactam bridges and disulfide or thioether staples achieve the same geometric effect.
The payoff is usually threefold: higher helical content by circular dichroism, higher affinity because the bound conformation is pre-organised, and protease resistance, since a locked helix never presents the extended backbone an enzyme needs. Some staples also confer cellular uptake, which is the point, since the intended targets are intracellular protein-protein interfaces. The most-advanced examples have been dual MDM2 and MDMX inhibitors intended to reactivate p53, which reached early-phase oncology trials.
That is also the honest limit of the field. Stapling has proven itself as a chemical technique and has produced clinical candidates, but no stapled peptide has yet become an approved drug, and results are strongly sequence-dependent: the same staple that rescues one helix can lower activity in another.
The overstatement to watch is uptake. Cell entry by stapled peptides is not a general property of the staple, it depends on the hydrophobicity and charge of the specific construct, and early claims were complicated by assays that could not distinguish material trapped in endosomes from material actually delivered to the cytosol.